Obesity and type 2 diabetes mellitus are national and worldwide epidemics. The physiological mechanisms that lead from obesity to abnormal glucose homeostasis and eventual type 2 diabetes mellitus remain elusive. Interestingly, accumulating evidence suggests that neurons within the hypothalamus are sensitive to peripheral nutrients and hormones such as insulin and leptin to regulate peripheral glucose homeostasis. These data point to the brain as an important link between obesity and type 2 diabetes mellitus. A wide range of evidence points to an important role for glucagon-like peptide-1 (GLP-1) in the control of glucose levels in the blood and this has resulted in the recent approval of long-acting GLP-1 analogs for the treatment of type 2 diabetes mellitus. GLP-1 is made in the intestine and the conventional model hypothesizes that it acts on peripheral receptors to increase insulin secretion. However, GLP-1 is also made in the brain and GLP-1 receptors are found in several key regions of the brain that have been linked to the control of peripheral glucose levels. In fact, preliminary data conducted by Dr. Sandoval suggest that GLP-1, is a central nervous system signal that regulates peripheral glucose levels. Therefore, this proposal is aimed at understanding the mechanisms that link the brain GLP-1 system to peripheral glucose homeostasis. Specifically, the goals of this proposal are: to determine which populations of neuronal GLP-1 receptors mediate the effect of GLP-1 on peripheral glucose levels;the degree to which changing glucose levels are due to central GLP-1 effects on the liver or pancreas;and the key intracellular mediators of central GLP-1's action on peripheral glucose levels. Finally, we will also determine whether the glucose impairments produced by diet-induced obesity are associated with impairments of central nervous system GLP-1 function. The long-term goals of this research are to elucidate the specific cellular and neuronal mechanisms that link obesity and type 2 diabetes mellitus. Further, the current proposal will provide Dr. Sandoval an ideal opportunity to add a number of basic research skills to her already well-developed human research expertise. This will allow her to pursue an independently funded career of hypothesis-driven translational research to elucidate the etiology and develop better treatment strategies for obesity and type 2 diabetes mellitus.